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Larry Wilson (Andrew McCarthy) and Richard Parker (Jonathan Silverman) are at a Manhattanmorgue where they see their deceased CEO Bernie Lomax (Terry Kiser). Larry falsely claims Bernie as his uncle, so he can get some of Bernie's possessions including Bernie's credit card. At the insurance company, Larry and Richard are quizzed by their boss and Arthur Hummel (Barry Bostwick), the company's internal investigator, who ask the two if they have the US$2 million that Bernie embezzled. They deny knowing where the money is, but their boss believes they're lying and fires them. He also sends Hummel after them, giving him two weeks to prove their guilt.

Over dinner (paid for with Bernie's credit card, in one of its many uses), Larry tells Richard he found a key to a safe deposit box in St. Thomas, U.S. Virgin Islands and asks Richard if he will use the computer at work to see if the $2 million is in Bernie's account. At first Richard refuses but ultimately gives in.

Meanwhile, in the Virgin Islands, a voodoo queen named Mobu (Novella Nelson) is hired by mobsters to find the money Bernie stole. She sends two servants—Henry (Steve James) and Charles (Tom Wright)—to go to New York, get Bernie's body, use a voodoo ceremony to reanimate him, and bring him back to her so he can lead her to the money. Their attempts to bring Bernie back are plagued by accidents. They prepare in a bathroom at a sleazy porno theater for a voodoo ceremony, but having lost the sacrificial chicken, they use a pigeon instead. This limits Bernie's ability to walk toward the hidden money: he only moves when he hears music. At the 42nd St-Grand Central subway station, Henry and Charles soon abandon him to chase a man who stole their boombox.

Later that night, Larry and Richard sneak into their office building to check Bernie's account, only to find that Bernie is the only one that can open it. They are soon arrested by the police for breaking and entering. After their release, they find Bernie (whom they believe is still dead), stuff him into a suitcase, bring him with them to the Virgin Islands, and put him into a small refrigerator in their hotel room. Unbeknownst to the two, Hummel is following them to recover the embezzled money. The guys successfully use Bernie to open his safety deposit box but they only find a map. Meanwhile, Larry befriends a lovely native girl named Claudia (Troy Beyer), and gives her the map. Later, he and Richard are captured by Henry and Charles, who take them to the Mobu. With one of the mobsters holding a gun to his head, she forces Richard to drink a poisonous concoction and tells them they must find the money by sundown to get the antidote.

When Larry, Richard, and Claudia are reunited, they are shocked to discover that Bernie is moving and realize he is leading them towards the money. To keep him moving, they put headphones on his head. As Bernie finds a large chest underwater, Larry accidentally shoots him in the head with an underwater speargun, destroying the headphones. They attempt to bring Bernie back to the surface but he will not let go of the chest, which is too heavy to hoist out of the water. They end up attaching Bernie to a horse carriage with music playing. It seems to work at first, but when they go downhill, the carriage goes out of control. Eventually, the carriage ends up at Mobu's compound. Bernie hits a large tree branch and spins himself into a somersault before knocking out Mobu. The crash also causes Bernie to drop the chest on the ground and it breaks open. Larry tries to scoop up the money but is caught by Hummel (now slightly unhinged upon seeing the undead Bernie walk) and he relinquishes the money to him. With Mobu out of commission, Claudia's father, a medical doctor, says that he can cure Richard if he can get the blood of a virgin (which Larry confesses he can provide). The mobsters and Mobu are arrested, and Bernie is last seen leading Henry and Charles, who have been transformed into goats by voodoo, in a carnival parade.

Larry confesses to Richard that he returned the $2 million to the insurance company, but only after learning Bernie actually stole $3 million. Larry and Richard use some of the remaining million to purchase a yacht crewed by attractive women.

The movie was filmed in 1992 in the Territory of the Virgin Islands of the United States and in New York City. The talent and staff, who were mainly from the Los Angeles area were on location when the Los Angeles riots of April 1992 broke out and they stated in a St. Thomas interview that they were worried for their loved ones. The Bernie dummy used in the film had been on display for the film's debut shortly before the riot's outbreak, and was robbed of its painter's hat and $400 sunglasses.[1]

Weekend at Bernie's II is mentioned in the eighth season episode of Seinfeld, "The Comeback". The movie is featured in the staff picks shelf at a video rental store, under "Gene's Picks". Kramer recommends it to Elaine (as "an hilarious premise") instead of a staff pick by "arthouse goon" Vincent. Elaine rents it, only to be disappointed and eventually yelling "Bernie's dead, you idiots!" at the television while watching it.

Similarly, in an episode of NCIS a character who needs to establish an alibi is too embarrassed to say which film he had been watching. The team assume he was watching a porn film, but he eventually admits it was Weekend at Bernie's II, to which film geek Agent DiNozzo says, "Even worse."[6]

The movie is referenced in the How I Met Your Mother episode "How Lily Stole Christmas" when Ted attempts to insult Lily for having a poor sense of humor. "Remember that time we heard her laughing, and we thought she was watching Weekend at Bernie's but it turned out she was watching Weekend at Bernie's II!" This movie is also referenced in the How I Met Your Mother episode "Weekend at Barney's".

The Rick and Morty episode "Rixty Minutes" features a trailer for Last Will and Testameow: Weekend at Dead Cat Lady's House II, seen on a television channel from an alternate dimension.

The movie is also referenced in the episode "HISTORY BONERS" of Funhaus show, Demo Disk. It was later referenced again in "WEEKEND AT BURNIE BURNS?" of the Funhaus show, Open Haus.

In 2016 filmmaker Jarret Gahan declared Weekend At Bernies II as one of his ultimate guilty pleasures on the FakeShemp.Net podcast.

Inspired by the movement of the movie's namesake, a style of dance was created called "Movin' Like Bernie". Homemade movies went viral on the internet, from children to soldiers serving overseas.[7] Even professional athletes began performing the dance, including Baltimore Ravens running back Ray Rice, after scoring a touchdown during a nationally-televised January 2011 game against the Pittsburgh Steelers.[8]

The 2012 Oakland Athletics have adapted "Movin' Like Bernie" into their celebration routines after Coco Crisp played the song for third baseman Brandon Inge in the team's clubhouse before a game. Players, such as Josh Reddick, will perform the dance after a home run, big hit or walk off victory.[9]